Occupational or environmental exposure to certain pollutants or chemicals can result in the development of toxic manifestations that can lead to various immune dysfunctions. Administration of several therapeutic drugs is also responsible for the occurrence of abnormal immune reactions. The mechanisms by which certain molecules or toxicants trigger a specific loss of tolerance to defined self-antigens in susceptible individuals are unknown. Chemically-induced autoimmunity in H-2S represents a unique experimental model for studying chemically- induced immune syndromes in humans. Mercuric chloride injection in H- 2S mice trigger a complex syndrome with polyclonal lymphocytic activation, hyperglobulinemia, immune complex deposits with proteinuria and production of highly specific autoantibodies to nucleolar antigens. Exploring this model will help us understand the mechanisms behind chemically-induced autoimmunity. The conventional view about chemically-induced autoimmunity is that the induction phase is Th2-mediated, whereas the resolution phase is Th1- dependent. Based upon our own preliminary data, we believe that this is an over-simplification of the problem and our hypothesis is that both the Th1 and Th2 subsets are involved in the induction of this syndrome. This has important therapeutic implications since treatment of human chemically-induced immune dysfunction would then have to be more refined than merely altering the Th1-Th2 balance. We will first test our hypothesis by identifying the cytokines that are expressed (both at the RNA and protein level) in this model. The importance of these cytokines in the manifestation of this syndrome will then be verified by manipulating their levels via anti-cytokine antibodies, antagonistic cytokines, and the use of cytokine knock-out mouse strains. Lastly, to determine the importance of cognate T-B interactions participate in the induction of this syndrome, we will investigate the role of co-stimulatory molecules, such as CD40 and B7-1/B7-2. These last experiments are also relevant to the unifying theme of this application, since interactions among different co-stimulatory molecules can bias an immune response towards the Th2 or Th2 pathway.